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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
  • C07C243/10—Hydrazines
  • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
  • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/044—Pyrrole radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

• This invention relates to novel indolopyrrolocarbazole derivatives which are useful in the field of medicine and, more specifically, inhibit the g rowth of tumor cells and thereby exhibit an anti tumor effect and a process for preparing them, and their use.
• the present inventors screened a wide variety of microbial metabolites, found a novel compound BE-13793C having antitumor activity (12,13-dihydro-1,11-dihydroxy-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione), and disclosed it [see Japanese Laid-Open Patent No. 20277/'91 and the Journal of Antibiotics, Vol. 44, pp. 723-728 (1991)].
• a problem to be solved by the present invention is to create a compound having more excellent antitumor activity than the indolopyrrolocarbazole-derived antitumor substances disclosed in the prior patent application (International Publication No. WO91/18003 and European Patent Laid-Open No. EP0545195 A1).
• the present inventors have synthesized a large number of indolopyrrolocarbazole derivatives and have examined their antitumor activities, with a view to creating a compound having more excellent antitumor activity than the indolopyrrolocarbazole-derived antitumor compounds which were previously disclosed.
• the compounds represented by the following general formula [I] are novel compounds having very excellent antitumor activity, stability and safety.
• the present invention relates to the compounds of the general formula wherein R 1 and R 2 each represent an OH group, R 1 is located at the 1- or 2-position, R 2 is located at the 10- or 11-position, R 2 is located at the 11-position when R 1 is located at the 1-position, and R 2 is located at the 10-position when R 1 is located at the 2-position, or pharmaceutically acceptable salts thereof, their intermediates, processes for preparing them, and their use.
• the compounds of the present invention and their intermediates can be prepared according to the process represented by the following procedure A .
• R 1 and R 2 each represent an OH group, provided that R 1 is located at the 1-or 2-position on the ring, R 2 i s located at the 10- or 11-position on the ring, R 2 is located at the 11-position when R 1 is located at the 1-position, and R 2 is located at the 10-position when R 1 is located at the 2-position.
• R 4 represents a hydrogen atom, a lower alkyl group, a benzyloxymethyl group or an aralkyl group.
• lower alkyl group means straight-chain or branched alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, sec-propyl, butyl, pentyl and hexyl.
• aralkyl group means aralkyl groups of 7 to 12 carbon atoms, such as benzyl, phenethyl and phenylpropyl.
• R 5 and R 6 each represent a protected OH group, provided that R 5 is located at the 1- or 2-position on the ring, R 6 is located at the 10- or 11-position on the ring, R 6 is located at the 11-position when R 5 is located at the 1-position, and R 6 is located at the 10-position when R 5 is located at the 2-position.
• Usable protecting groups include, for example, benzyl, tolyl, p-methoxybenzyl and benzyloxymethyl groups.
• R 7 to R 10 may be the same or different and each represent a protecting group for an OH group .
• Usable protecting groups include, for example, benzyl, tolyl, p-methoxybenzyl and benzyloxymethyl groups.
• R 12 represents a protecting group for the amino group of an indole skeleton. Examples of the protecting group are the same as described above.
• X represents a leaving group. Examples thereof include chlorine, bromine and iodine atoms.
• the organometallic compound which is used to prepare a compound of the general formula [XI] or the like by reacting a maleimide compound of the general formula [IX] or the like with an indole compound of the general formula [X] or the like can be, for example, an alkyl lithium such as butyl lithium; lithium diisopropylamide; an alkali metal hexaalkyldisilazide such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or a Grignard reagent such as ethylmagnesium bromide or methylmagnesium chloride.
• an alkyl lithium such as butyl lithium
• lithium diisopropylamide an alkali metal hexaalkyldisilazide
• an alkali metal hexaalkyldisilazide such as lithium hexamethyldisilazide
• the Mitsunobu reaction is a reaction for forming a glycoside linkage by using an organic phosphine such as triphenylphosphine or tributylphosphine, and an azodicarboxylic acid derivative such as azodicarboxylic acid diethyl ester, azodicarboxylic acid di-tert-butyl ester, azodicarboxylic acid diisopropyl ester, azodicarboxylic acid di-N,N-dimethylamide or azodicarboxylic acid di-N-methylpiperazinamide (see Synthesis, I, 1981, pp. 1-28).
• an organic phosphine such as triphenylphosphine or tributylphosphine
• an azodicarboxylic acid derivative such as azodicarboxylic acid diethyl ester, azodicarboxylic acid di-tert-butyl ester, azodicarboxylic acid diiso
• the oxidizing agent which is used to react a compound of the general formula [XVII] or the like having two indole skeletons with an oxidizing agent and thereby convert it to an indolopyrrolocarbazole compound of the general formula [XVIII] or the like can be 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (hereinafter abbreviated as DDQ) , CuCl 2 , Cu(OAc) 2 , Cu(NO 2 ) 2 , PdCl 2 , Pd(OAc) 2 , Pd(CF 3 COO) 2 or the like.
• DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
• reaction of a maleimide compound of the general formula [IX] with an indole compound of the general formula [X] can be carried out with the aid of an alkali metal hexaalkyldisilazide such as lithium hexamethyldisilazide, or a Grignard reagent such as ethylmagnesium bromide.
• alkali metal hexaalkyldisilazide such as lithium hexamethyldisilazide
• a Grignard reagent such as ethylmagnesium bromide.
• the solvents which can be used in this reaction include toluene, benzene, tetrahydrofuran (THF), dioxane, diethyl ether and the like.
• the reaction temperature may usually range from -78°C to 130°C and preferably from -20°C to 110°C.
• a compound of the general formula [XII] can be prepared by introducing a protecting group for the amino group of the indole skeleton in a compound of the general formula [XI].
• the protective agent used for this purpose can be a halide or acid anhydride corresponding to the aforesaid protecting group.
• Preferred examples thereof include di-tert-butyl dicarbonate and tert-butyloxycarbonyl chloride.
• This reaction is preferably carried out in the presence of a base such as 4-N,N-dimethylaminopyridine.
• a base such as 4-N,N-dimethylaminopyridine.
• the solvents which can be used in this reaction include toluene, benzene, THF, dioxane, ether and the like.
• the reaction temperature may usually range from -78°C to 100°C and preferably from -25°C to 25°C.
• the reaction of the compound of the general formula [XIV] with a compound of the general formula [XV] can be carried out according to the so-called Mitsunobu reaction.
• organic phosphines and azodicarboxylic acid derivatives as described above.
• Preferred examples of the organic phosphines include tributylphosphine and triphenylphosphine
• preferred examples of the azodicarboxylic acid derivatives include azodicarboxylic acid diethyl ester and azodicarboxylic acid diisopropyl ester.
• reaction solvent THF, dioxane, ether and the like may preferably be used.
• the reaction temperature may usually range from -78°C to 50°C and preferably from -40°C to 20°C.
• the deprotection of the amino group of an indole skeleton in a compound of the general formula [XVI] is preferably carried out under conditions which permit selective deprotection.
• conditions which permit selective deprotection For example, it is preferable to employ acidic or basic conditions which permit the tert-butoxycarbonyl , 2-trimethylsilylethoxymethyl or other group on the amino group to be selectively removed while retaining the other protecting groups.
• acids such as trifluoroacetic acid and HF
• bases such as methylamine, tert-butoxypotassium and tetra-n-butyl ammonium fluoride.
• a compound of the general formula [XVIII] can be prepared by oxidatively cyclizing a compound of the general formula [XVII].
• the oxidizing agents which can be used in this reaction include, for example, DDQ, CuCl 2 , Cu(OAc) 2 , Cu(NO 2 ) 2 , PdCl 2 , Pd(OAc) 2 and Pd(CF 3 COO) 2 as described above.
• As the reaction solvent there may be used toluene, methylene chloride, dimethylformamide, dioxane, ether and the like.
• the reaction temperature may usually range from 0°C to 100°C.
• the removal of the protecting groups for the phenolic hydroxyl groups and the glycosyl group in the compound of the general formula [XVIII] can be carried out under acidic conditions or by well-known common hydrogenation reaction or the like.
• a compound of the general formula [XX] can be prepared by reacting a compound of the general formula [XIX] with a base.
• the bases which can be used in this reaction include NaOH, KOH, K 2 CO 3 , Na 2 CO 3 , NaHCO 3 and the like.
• the solvents which can be used therein include water, methanol, ethanol, dimethylformamide and the like.
• the reaction temperature may usually range from 0°C to the boiling point of the solvent.
• a compound of the general formula [I] can be prepared by reacting the compound of the general formula [XX] wi th H 2 NNHCH(CH 2 OH) 2 .
• the sol vents which can be used in this reaction include methanol, ethanol, THF, dimethylformamide and the like.
• the reaction temperature may usually range from 0°C to the boiling point of the solvent.
• H 2 NNHCH(CH 2 OH) 2 used is usually in the range of 1 to 3 molar equivalents based on the compound [XX]. If necessary, this compound may be used in smaller or larger amounts.
• H 2 NNHCH(CH 2 OH) 2 can be prepared, for example, according to the procedure described in Example 3.
• a cell culture medium (RPMI-1640 medium containing 10% bovine fetal serum) containing 1 ⁇ 10 3 mouse leukemia cells (P388), human gastric cancer cells (MKN-45), human pulmonary cancer cells (PC-13) or human rectal cancer cells (DLD-1) was pipetted into the wells of a 96-well microplate, and in cubated at 37°C under 5% CO 2 for 24 hours . Then, 50 ⁇ l of a test solution containing each test compound was added, and the culture medium was further incubated at 37°C under 5% CO 2 for 72 hours.
• RPMI-1640 medium containing 10% bovine fetal serum containing 1 ⁇ 10 3 mouse leukemia cells (P388), human gastric cancer cells (MKN-45), human pulmonary cancer cells (PC-13) or human rectal cancer cells (DLD-1) was pipetted into the wells of a 96-well microplate, and in cubated at 37°C under 5% CO 2 for 24 hours . Then
• a MKN-45 solid tumor which had previously been grown by transplantation under the skin of a nude mouse was minced, and 3 mm cubes of the tumor were transplanted under the skin of mice used for this test.
• a treatment was carried out by injecting a dose of each test drug into the caudal vein of the mice, once a day, for 5 consecutive days and, after two days' pause, injecting the test drug for 5 days (treatment schedule: 5/w ⁇ 2 ) or four times at intervals of 3 or 4 days (treatment schedule: 2/w ⁇ 2) .
• the compounds provided by the present invention exhibit a more excellent antitumor effect than the control compound.
• the compounds of the present invention exhibit an excellent antitumor effect and are hence useful as antitumor agents for the prophylaxis or treatment of diseases and, in particular, for the treatment of cancer.
• the compounds of the present invention may usually be combined with pharmaceutically acceptable carriers or excipients to make pharmaceutical preparations containing them in effective amounts.
• the compounds of the present invention can be used as antitumor agents in various dosage forms. They include, for example, oral preparations such as tablets, capsules, powders, granules and waters; parenteral liquid preparations such as sterilized solutions and suspensions; suppositories; and ointments.
• Solid preparations may be made by forming the compounds of the present invention directly into tablets, capsules, granules or powder.
• suitable additives include sugars such as lactose and glucose; starches such as corn, wheat and rice; fatty acids such as stearic acid; inorganic salts such as magnesium aluminate metasilicate and anhydrous calcium phosphate; synthetic polymers such as polyvinyl pyrrolidone and polyalkylene glycol; fatty acid salts such as calcium stearate and magnesium stearate; alcohols such as stearyl alcohol and benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose and hydroxypropylmethylcellulose; and other commonly used additives such as gelatin, talc, vegetable oils and gum arabic.
• These solid preparations such as tablets, capsules, granules and powders may generally contain the active ingredient in an amount of 0.1 to 100% by weight and preferably 5 to 100% by weight.
• the compounds of the present invention may be formed into suspensions, syrups, injections or infusions with the aid of suitable additives commonly used in liquid preparations, such as water, alcohols and vegetable oils (e.g., soybean oil, peanut oil and sesame oil).
• suitable additives commonly used in liquid preparations, such as water, alcohols and vegetable oils (e.g., soybean oil, peanut oil and sesame oil).
• suitable solvents include, for example; distilled water for injection, an aqueous solution of lidocaine hydrochloride (for intramuscular injection), physiological saline, an aqueous glucose solution, ethanol, polyethylene glycol, liquids for intravenous injection (e.g., aqueous solutions of citric acid and sodium citrate) and electrolyte solutions (for intravenous drip infusion and intravenous injection), as well as mixtures thereof .
• injections may be prepared not only in previously dissolved form, but also in the form of a powder or mixture with suitable additives for dissolution prior to use. These injections may usually contain the active ingredient in an amount of 0.1 to 10% by weight and preferably 1 to 5% by weight.
• Liquid preparations for oral administration such as suspensions and syrups, may usually contain the active ingredient in an amount of 0.5 to 10% by weight.
• the preferred dosages of the compounds of the present invention may vary according to the type of the compound used, the type of the composition prepared, the frequency of use, the site to be treated, the severity of symptoms, the age of the patient, the diagnosis made by the doctor, the type of the tumor, and the like.
• their daily dose for adults may be in the range of 1 to 800 mg for oral administration, and in the range of 0.1 to 500 mg for parenteral administration and preferably for intravenous injection.
• These daily doses may be given at a time or in 2 to 5 divided doses, depending on the method of administration and the severity of symptoms. Alternatively, they may be administered intermittently, for example, every second or third day.
• This compound was prepared according to a method comprising the following steps 1) to 9).
• This compound was prepared according to a method comprising the following steps 1) to 9).
• the compounds of the present invention have an excellent antitumor effect and are hence useful as antitumor agents in the field of medicine.

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